HIV lipodystrophy (LD) is a common complication of HIV infection and its therapy. It is characterized by extensive subcutaneous fat loss and is associated with insulin resistance, diabetes and hypertriglyceridemia. We have found that HIV LD is also associated with increased resting (REE) and total daily energy expenditure. Such increases in EE have also been found in congenital forms of LD but the pathogenesis is unknown. However, we have recently shown that subjects with HIV LD uniquely respond to short-term under- and overfeeding with significant decreases and increases in REE, respectively. The elevated REE of HIV LD and its responsiveness to changes in caloric intake may represent true forms of adaptive thermogenesis in this important component of total daily energy expenditure. This adaptive thermogenesis may be a response to an inability to store triglyceride fuel in a normal manner secondary to extensive loss/dysfunction of subcutaneous adipose tissue. Insights into the mechanism(s) underlying this adaptation would have great relevance to weight regulation in general and to the epidemic conditions of overweight and obesity. In this application, we will determine if the sympathetic nervous system contributes more to the support of REE in subjects with HIV LD and hypermetabolism compared to HIV-infected and healthy controls. We will also determine if there is increased mitochondrial uncoupling in the skeletal muscle of cases vs controls. Increased mitochondrial uncoupling dissipates calories as heat and leads to increased REE. Therefore, this could a potential mechanism behind the hypermetabolism of HIV LD. In addition to these mechanistic studies, we will also test the energetic response to and substrate oxidation pattern during both high-fat and high-carbohydrate overfeeding in patients with HIV LD. We hypothesize that overfeeding of both macronutrients will be associated with significant increases in REE and TEE in those with LD but not in controls. We also anticipate that high-fat overfeeding will lead to significant increases in fat oxidation in LD subjects but not in controls. Finally, we will determine if HIV LD is associated with increased oxidative stress. HIV LD is a hypermetabolic state, and since reactive oxygen species are a normal byproduct of oxygen consumption, it is plausible that this syndrome will be associated with increased oxidative stress. This is especially relevant in this population already at increased risk of diabetes and atherosclerotic vascular disease as oxidative stress may play a role in these disease processes. PUBLIC HEALTH RELEVANCE: Patients with HIV lipodystrophy have both abnormally low amounts and dysfunction of their subcutaneous adipose tissue. They also have a higher then normal metabolic rate. This increased metabolic rate may be a form of adaptive thermogenesis. In other words, these patients may convert calories to heat instead of storing them because their subcutaneous adipose tissue cannot store the calories as fat. If this could be better understood, our findings would have broad relevance to the field of obesity in general and could open up new avenues of treatment for this common problem.